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Osimertinib for the T790M Resistance Mutation

Panelists:Benjamin P. Levy, MD, Mount Sinai Health Systems;Chandra P. Belani, MD, Penn State Cancer Institute;Marina Garassino, MD, National Cancer Institute Milan, Italy;Sarah B. Goldberg, MD, MPH, Yale Cancer Center;Ramaswamy Govindan, MD, Washington University School of Medicine;Mark G. Kris, MD, Memorial Sloan-Kettering Cancer Center
Published: Tuesday, Aug 23, 2016


Transcript:

Benjamin P. Levy, MD:
As you mentioned, Marina, we do have now a very actionable relevant mutation in the resistant setting, with T790M. And, it occurs in up to two-thirds of patients who develop resistance on an EGFR TKI. Chandra, do you want to talk about the importance of why we need to identify this, what we’re doing with this information in terms of the new drug, and where we sit with this drug right now?

Chandra P. Belani, MD: I think, osimertinib, which also is called AZD9291, is a third-generation EGFR inhibitor which not only targets the EGFR sensitizing mutations—which are in exon 19 and 21—but also targets the T790M resistance mutation. So, I think we are fortunate to have that drug. And the drug approval was based on the study where osimertinib showed an overall response rate close to 60% in expanded cohorts in this phase I/II trial. The overall median progression-free survival was 9.6 months, as far as I remember. Mainly the responses are seen in patients who had T790M mutations because the response rate in patients who were negative for T790M, was only 21%. And, the median progression-free survival in that population was 2.8 months.

I think that we have this drug now, which targets a specific resistant mutation—T790M—and has impressive and provocative degrees of both the response rate and progression-free survival. In addition, actually, as it targets both the sensitizing mutations in exon 19 and exon 21, it has also shown a benefit in the frontline setting. In the frontline setting, the response rates have been as high at 70%—in two cohorts, 60% and 80%. The data are early there, but with disease control rates that approach 97% to 100%, I think it is impressive. Whether osimertinib will replace the first-generation inhibitors is yet to be determined.

Benjamin P. Levy, MD: Could you talk a little bit about the toxicity profile as well, in the context of first- and second-generation TKIs—what we’re seeing or what you’re witnessing in your practice and what we saw in the data?

Chandra P. Belani, MD: So, actually the toxicity profile is pretty good for these third-generation inhibitors, especially osimertinib because, it spares wild-type EGFR. Although you see some element of diarrhea and rash. But, it is not as what you see with the first-generation inhibitors.

Mark G. Kris, MD: If I could just add to that. You’ve got to have a control group because all the patients to date have had a lot of resistance. I have to say, in my practice, all but one said it’s easy.

Sarah B. Goldberg, MD, MPH: I agree.

Mark G. Kris, MD: Of course, it’s human beings. One of them said it was harder.

Chandra P. Belani, MD: I think because of its wild-type—sparing effect, the toxicities that have been seen are pneumonitis to the extent of about 2% in the study. And, there is some element of QT prolongation, as seen with other TKIs. So, I think those are the two main toxicities which have been seen with the drug. But, overall, it is a wonderful drug which is fairly well tolerated. And, in oncology, it’s probably one of the first ones to have so little toxicity.

Benjamin P. Levy, MD: I’ve been very encouraged by both its efficacy and its adverse event profile. We participated in the EAP, and, importantly, in that study they allowed plasma testing only. We identified all of our patients for that trial based on plasma. Plasma is reliable. If it’s positive, you can use that to drive treatment decisions. But, the toxicity profiles, as Mark mentioned, in the context of first-generation TKIs is much better tolerated. So, I think it’s been a win for patients and for physicians.

Mark G. Kris, MD: I think we’ve become too tolerant of the rash and diarrhea. It really does affect our patients. First off, the rash is obvious. And, then, secondly, how many people have to change their day because of the diarrhea? When I have the big meeting, I have to do this. They think about these things. And if we have a way around it, and if you take that concern out of their lives, I think that’s a good thing. Again, helping to make my case for giving these drugs upfront. But, we underestimate how lifestyle-disrupting the rash and diarrhea are. And taking doxycycline for the rest of your life, and smearing yourself with Aclovate five times a day, you know that’s not wonderful.

Sarah B. Goldberg, MD, MPH: It’s interesting. When we were talking about the oligoprogression patients, I agree with what you were saying. My standard has been that if there’s just one or two sites of progression, try to radiate, and then continue on with what you were doing to try to get the most out of it. But, now with this, the new generation of drugs, I’m not sure it makes sense to get the most out of it. Maybe it makes sense to switch then. I don’t know. I think this is a case-by-case discussion. But, if there’s progression at one site and we know these drugs are so much better tolerated, maybe it makes some sense to switch them earlier.

Transcript Edited for Clarity
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Transcript:

Benjamin P. Levy, MD:
As you mentioned, Marina, we do have now a very actionable relevant mutation in the resistant setting, with T790M. And, it occurs in up to two-thirds of patients who develop resistance on an EGFR TKI. Chandra, do you want to talk about the importance of why we need to identify this, what we’re doing with this information in terms of the new drug, and where we sit with this drug right now?

Chandra P. Belani, MD: I think, osimertinib, which also is called AZD9291, is a third-generation EGFR inhibitor which not only targets the EGFR sensitizing mutations—which are in exon 19 and 21—but also targets the T790M resistance mutation. So, I think we are fortunate to have that drug. And the drug approval was based on the study where osimertinib showed an overall response rate close to 60% in expanded cohorts in this phase I/II trial. The overall median progression-free survival was 9.6 months, as far as I remember. Mainly the responses are seen in patients who had T790M mutations because the response rate in patients who were negative for T790M, was only 21%. And, the median progression-free survival in that population was 2.8 months.

I think that we have this drug now, which targets a specific resistant mutation—T790M—and has impressive and provocative degrees of both the response rate and progression-free survival. In addition, actually, as it targets both the sensitizing mutations in exon 19 and exon 21, it has also shown a benefit in the frontline setting. In the frontline setting, the response rates have been as high at 70%—in two cohorts, 60% and 80%. The data are early there, but with disease control rates that approach 97% to 100%, I think it is impressive. Whether osimertinib will replace the first-generation inhibitors is yet to be determined.

Benjamin P. Levy, MD: Could you talk a little bit about the toxicity profile as well, in the context of first- and second-generation TKIs—what we’re seeing or what you’re witnessing in your practice and what we saw in the data?

Chandra P. Belani, MD: So, actually the toxicity profile is pretty good for these third-generation inhibitors, especially osimertinib because, it spares wild-type EGFR. Although you see some element of diarrhea and rash. But, it is not as what you see with the first-generation inhibitors.

Mark G. Kris, MD: If I could just add to that. You’ve got to have a control group because all the patients to date have had a lot of resistance. I have to say, in my practice, all but one said it’s easy.

Sarah B. Goldberg, MD, MPH: I agree.

Mark G. Kris, MD: Of course, it’s human beings. One of them said it was harder.

Chandra P. Belani, MD: I think because of its wild-type—sparing effect, the toxicities that have been seen are pneumonitis to the extent of about 2% in the study. And, there is some element of QT prolongation, as seen with other TKIs. So, I think those are the two main toxicities which have been seen with the drug. But, overall, it is a wonderful drug which is fairly well tolerated. And, in oncology, it’s probably one of the first ones to have so little toxicity.

Benjamin P. Levy, MD: I’ve been very encouraged by both its efficacy and its adverse event profile. We participated in the EAP, and, importantly, in that study they allowed plasma testing only. We identified all of our patients for that trial based on plasma. Plasma is reliable. If it’s positive, you can use that to drive treatment decisions. But, the toxicity profiles, as Mark mentioned, in the context of first-generation TKIs is much better tolerated. So, I think it’s been a win for patients and for physicians.

Mark G. Kris, MD: I think we’ve become too tolerant of the rash and diarrhea. It really does affect our patients. First off, the rash is obvious. And, then, secondly, how many people have to change their day because of the diarrhea? When I have the big meeting, I have to do this. They think about these things. And if we have a way around it, and if you take that concern out of their lives, I think that’s a good thing. Again, helping to make my case for giving these drugs upfront. But, we underestimate how lifestyle-disrupting the rash and diarrhea are. And taking doxycycline for the rest of your life, and smearing yourself with Aclovate five times a day, you know that’s not wonderful.

Sarah B. Goldberg, MD, MPH: It’s interesting. When we were talking about the oligoprogression patients, I agree with what you were saying. My standard has been that if there’s just one or two sites of progression, try to radiate, and then continue on with what you were doing to try to get the most out of it. But, now with this, the new generation of drugs, I’m not sure it makes sense to get the most out of it. Maybe it makes sense to switch then. I don’t know. I think this is a case-by-case discussion. But, if there’s progression at one site and we know these drugs are so much better tolerated, maybe it makes some sense to switch them earlier.

Transcript Edited for Clarity
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